Head and Neck Squamous Cell Carcinoma (HNSCC) is a leading cause of cancer deaths worldwide and recent unbiased comprehensive genomic characterizations of HNSCC revealed that TP53 is the most common somatically mutated gene in this tumor type. The main objective of this project is to explore novel ways to improve the outcome of HNSCC patients who harbor deleterious TP53 mutations. While it has been established that HNSCC patients harboring TP53 mutations tend to have poor therapeutic response, efforts to utilize p53 mutational status as a clinical biomarker to guide therapy have been unsuccessful thus far due to the complex heterogeneity of TP53 mutations. We have developed a novel TP53 scoring algorithm based upon evolutionary action (EAp53) that can accurately stratify patients as high or low risk subtypes, which we hypothesize will predict survival, therapeutic response and treatment failure in HNSCC patients. In this application, we first propose to validate this EAp53 scoring system in several HNSCC patient cohorts and in preclinical models. Moreover, we propose to demonstrate that the promising Wee-1 kinase inhibitor currently being used in clinical trials, MK-1775, in combination with cisplatin and/or radiation can overcome the high risk mutant p53-mediated resistance to chemotherapy or radiation in HNSCC using in vitro and in vivo models. We shall also examine the cellular and molecular mechanisms by which Wee-1 kinase inhibition sensitizes HNSCC to cisplatin and/or radiation treatment. Our work may have far reaching clinical significance by enabling identification of patients least likely to benefit from contemporary treatment strategies. In addition, we will overcome resistance to chemotherapy and radiation through synthetic lethal strategies targeting DNA repair and discover mechanisms driving the response of tumor cells to DNA damaging agents in the presence of Wee 1 kinase inhibition which could improve future cancer treatment.